Rebamipide Does Not Protect Against Naproxen-Induced Gastric Damage: a Randomized Double-Blind Controlled Trial Thiago Gagliano-Jucá1*, Ronilson A
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Gagliano-Jucá et al. BMC Gastroenterology (2016) 16:58 DOI 10.1186/s12876-016-0472-x RESEARCH ARTICLE Open Access Rebamipide does not protect against naproxen-induced gastric damage: a randomized double-blind controlled trial Thiago Gagliano-Jucá1*, Ronilson A. Moreno2, Tiago Zaminelli3, Mauro Napolitano4, Antônio Frederico N. Magalhães5, Aloísio Carvalhaes6, Miriam S. Trevisan5,JohnL.Wallace7 and Gilberto De Nucci3,7,8 Abstract Background: Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. Methods: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. Results: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95%CI = −1to0;p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 ± 129 pg/mL before treatment and 241 ± 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 ± 109 pg/mL before treatment, and 168 ± 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95%CI from −334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Conclusion: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers. Trial registration: ClinicalTrials.gov, NCT02632812. Registered 14 December 2015. Keywords: NSAID, Histopathology, Human, ELISA, Endoscopy, Cryer score, Modified Lanza score * Correspondence: [email protected] 1Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro (UFRJ), 21941-902 Rio de Janeiro, Brazil Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gagliano-Jucá et al. BMC Gastroenterology (2016) 16:58 Page 2 of 7 Background After performing a preliminary gastroduodenal endos- Naproxen and other non-selective non-steroidal anti- copy at the Vera Cruz Hospital (Campinas, Brazil) to inflammatory drugs (NSAIDs) induce gastrointestinal rule-out prior macroscopic upper GI damage in the (GI) adverse events ranging from dyspepsia to upper and subjects, twenty-four healthy volunteers (12 men) were lower GI tract ulcers [1–3]. Naproxen 660 – 1000 mg enrolled in the study. Other exclusion criteria were: per day administered for 2 to 14 days is used as a model achlorhydria (pH > 6.5); positive fecal occult blood test; for NSAID-induced gastroduodenal damage in healthy drug abuse, including alcohol or tobacco. volunteers [4–8]. Rebamipide has been described as a GI mucosal pro- Treatment tector agent with promising results in prophylaxis and Volunteers were randomly divided into 2 groups: group treatment of GI ulcers caused by NSAIDs, H. pylori or A received 550 mg of sodium naproxen (Flanax® - Bayer) endoscopic submucosal dissection [9–15]. Results from plus an effervescent placebo (Biolab Indústria Farmacêu- animal studies have suggested that the protective effects tica Ltda.) diluted in 200 mL of water b.i.d. for 7 con- of rebamipide are attributable to stimulation of prosta- secutive days; group B received 550 mg of sodium glandin (PG) synthesis [16, 17]. In healthy volunteers, naproxen (Flanax® - Bayer) plus 100 mg of effervescent concomitant administration of rebamipide 100 mg with rebamipide (Biolab Indústria Farmacêutica Ltda.) diluted ibuprofen 600 mg t.i.d. for 7 consecutive days resulted in in 200 mL of water b.i.d. for 7 consecutive days. The a mean gastric damage score of 1.3 ± 1.0, which was randomization sequence was determined using the significantly lower than that of the control group (mean randomization generator available at www.randomiza- score of 2.9 ± 1.7), as assessed by the modified Lanza tion.com, using 3 blocks of 8 subjects each. Volunteers score (p = 0.032) [10]. In patients with rheumatic disease were blind to whether they were receiving rebamipide or rebamipide 100 mg b.i.d. also showed a protective effect placebo. To assure adherence, the drugs were adminis- against NSAID-induced gastric damage [18]. tered by a member of the research team (also blind to The present study evaluated whether rebamipide could treatment allocation) early in the morning and late in provide a protective effect against naproxen-induced the evening for the whole duration of the study. A gastric damage in healthy volunteers. pharmacist was responsible for labeling treatments as A or B, and for breaking the code at the end of the study. Methods Volunteers were required to be fasted in the morning Volunteers and were only allowed to eat at least 2 h after adminis- Volunteers of both sexes aged 18 years old or older tration of medications. In the evening, volunteers were without any significant cardiac, hepatic, renal, pulmon- required to be at least for 2 h without ingestion of food, ary, neurological, gastrointestinal or hematological dis- and were also asked to avoid eating for the following 2 h eases, as determined by their medical history, physical after the dose. examination, and routine laboratory tests (hematology, Adverse reactions were individually evaluated. Causal- blood biochemistry, urine analysis and fecal occult blood ity relationship to the treatment was assessed with the test), were invited to participate in this double-blind, aid of the Karch & Lasagna algorithm [19]. The necessity randomized, parallel placebo-controlled phase II single- of interruption of treatment or specific therapy was indi- center trial. All subjects tested negative for hepatitis B vidually assessed by the Principal Investigator depending and C (except for serologic scar), as well as HIV I and II, on the severity of the reaction and the causality relation- and were instructed to abstain from taking any medica- ship to the treatment. tion including over-the-counter medication for 2 weeks prior to and during the study period. Pregnancy was an Gastrointestinal damage evaluation exclusion criterion. All women enrolled had negative β- Gastroduodenal endoscopy was performed before the HCG. All volunteers were informed about the aim and start of the study and in the morning of the 8th day of risks of the study by the clinical investigator and they all treatment in all volunteers. Exams were performed by a signed a written informed consent statement before enter- single endoscopist. The primary outcome measure of the ing the study. The study was performed according to the trial was the macroscopic damage observed in each 2008 revised Declaration of Helsinki for bio-medical re- treatment group at the end of treatment. The number of search involving human subjects and the 1996 rules of mucosal erosions after treatment was counted and Good Clinical Practices. The study protocol was approved macroscopic mucosal injury scored according to Cryer by the Committee of Research Ethics of the University of [20] and to the modified Lanza score (MLS; Table 1) Sao Paulo, Sao Paulo, Brazil, on 26 November 2014 [9, 21]. Gastroduodenal ulcers were classified according (before the initiation of the study procedures), and the to the Sakita-Miwa classification. Additionally, a second study is registered at ClinicalTrials.gov, ID NCT02632812. endoscopist retrospectively evaluated the exams, blind to Gagliano-Jucá et al. BMC Gastroenterology (2016) 16:58 Page 3 of 7 Table 1 Cryer and modified Lanza scores according to Chemical Monoclonal Prostaglandin E2 EIA Kit (item gastroduodenal mucosal injury number 514010). Briefly, biopsies from the gastric an- Score Cryer score Modified Lanza score trum and corpus collected in both endoscopic proce- 0 Normal or erythema No hemorrhage or erosion dures were weighted and homogenized individually for observed 20 s by a Polytron in 1 mL of Na3PO4 buffer solution 1 Any amount of submucosal One or two hemorrhages or (pH = 7.4). Aliquots of 200 μL of the homogenate were hemorrhage or edema without erosions observed in one placed in a dry bath at 37 °C for 20 min and then centri- erosions. gastric area. fuged at 20,800 g for 30 s. Supernatant (150 μL) was col- 2 1 erosion ± submucosal Three to five hemorrhages or lected and diluted 1:100 (v/v) to be used in the ELISA. hemorrhage or edema. erosions observed in one gastric area. Each aliquot was assayed in duplicate and final PGE2 32–4 erosions ± submucosal Hemorrhages or erosions concentrations were adjusted for initial sample mass.